The false hope of “right-to-try” metastasizes to Michigan

State “right-to-try” bills are springing up like kudzu all over the US. Their advocates promise that they will save lives by allowing terminally ill patients access to experimental therapeutics, when in fact they are highly unlikely to do any such thing given that the federal government, not the states, controls drug approval. In reality, right-to-try laws are a cruel sham that will do no such thing and lack even basic protections for desperate patients. Their purpose is to build political pressure to neuter the FDA. Unfortunately, right-to-try bills nearly always pass, as one just did in Michigan.

There are times when supporting science-based health policy and opposing health policies that sound compassionate but are not are easily portrayed as though I’m opposing mom, apple pie, and the American flag. One such type of misguided policy that I’ve opposed is a category of bills that have been finding their way into state legislatures lately known as “right to try” bills. Jann Bellamy and I have both written about them before, and with the passage of the first such bill into law in Colorado in May, I had been meaning to revisit the topic. Although “right-to-try” laws are a bad policy idea that’s not new, versions of such bills having been championed by, for example, the Abigail Alliance for at least a decade, the recent popularity of the movie Dallas Buyers Club appears to have given them a new boost, such that Colorado state Senator Irene Aguilar even frequently referred to her state’s right-to-try bill as the “Dallas Buyers Club” bill. It’s a topic I’ve been meaning to revisit since the news out of Colorado, but apparently I needed a nudge, given that it’s two months later now.

Unfortunately, that nudge came in the form of a right-to-try bill (Senate Bill 991) being introduced into the legislature in Michigan by Senator John Pappageorge and unanimously passing, almost without comment by the committee and certainly with minimal news coverage, through the first hurdle, the Michigan Senate Health Policy Committee. In parallel, the same legislation (House Bill 5651) has been introduced into the Michigan House of Representatives.
I joke (somewhat grimly) about seeming to be opposing mom, apple pie, and the American flag (not to mention apparently also about wanting to disembowel puppies) when I discuss right-to-try bills, but there’s a reason for that. These bills tend to have not just broad bipartisan support in the legislature, because opposing such laws seems on the surface to be the equivalent of denying dying patients a last ditch chance at life, but broad support among the public because of the seemingly reasonable question, “What’s the harm?” Unfortunately, disaster can result when normal human compassion for fellow suffering humans is yoked to misinformation and misunderstanding of science (in this case how clinical trials work), who really controls drug development and regulation in the US, and the real harm that using such drugs prematurely can cause. For right-to-try, the result is perniciously popular legislation that provides lots of false hope and virtually no benefit to terminally ill patients. In the face of this, even politicians with a reasonable understanding of the science, why such laws represent nothing but false hope, and why, even if they go into effect without objection by the FDA, would be far more likely to harm patients than help them, hesitate.

Right-to-try in Colorado

Before I get to my own state, let’s look at Colorado’s right-to-try law. One thing that I feel obligated to point out again is that virtually all the recent “right-to-try” bills introduced into state legislature have been based on model legislation designed by the Goldwater Institute, a libertarian think tank whose specious and misleading arguments for such legislation I’ve discussed before and will revisit and update in this post. In her previous post on right-to-try bills, Jann Bellamy mentioned that there is “nothing like a touching anecdote to spur a politician into action,” and she’s right. That’s why the Goldwater Institute’s web page on its right-to-try initiatives is populated with heart-wrenching testimonials of mostly cancer patients arguing that, if only they had had access to experimental drugs, they might survive or of patients who died whose families tearfully argue that “if only” right to try had been in place their loved ones might not have died. In the wake of the passage of Colorado’s right-to-try law in May, anecdotes ruled, heart-wrenching anecdotes such as this one about Nick Auden, a Colorado man with stage IV melanoma who died six months before the legislation passed:

Who isn’t moved by the struggles of a father who wants to survive for his children? Who wouldn’t want to help this man? What kind of monster am I to oppose a law that would provide brave suffering patients like Nick Auden another shot at life, no matter how slim the chance? Such is the level of discourse directed at those who have the temerity to point out that right-to-try laws are a sham, false hope, and far more likely to harm terminally ill patients than help them; that is, if they have any effect whatsoever, which is unlikely. They are what I like to call placebo laws in that they make the body politic feel better but have no real effect on the underlying problem that they are meant to address. Indeed, as Jann Bellamy pointed out, a much less emotion-driven analysis of these so-called “right-to-try” bills currently before several state legislatures reveals disturbing truths about the false promises behind these bills, promises which in some cases appear to be driven more by political ideology than genuine concern for patients.

This can be seen by a simple comparison of the text of the Goldwater Institute model legislation and the final text of the Colorado right-to-try law as enacted. The Colorado law, in fact, bears a very close similarity to the Goldwater Institute model legislation. Some differences between the Goldwater Institute template and the actual Colorado law that leapt out at me included that the Colorado law:

Adds a mention that the drug approval process in the US “protects future patients from premature, ineffective, and unsafe medications and treatments over the long run, but the process” (not in the Goldwater template text) and “often takes many years” (in the Goldwater text)

Alters eligibility to include patients who have “been unable to participate in a clinical trial for the terminal illness within one hundred miles of the patient’s home address for the terminal illness, or not been accepted to the clinical trial within one week of completion of the clinical trial application process”

States that “an insurer may deny coverage to an eligible patient from the time the eligible patient begins use of the investigational drug, biologic product, or device through a period not to exceed six months from the time the investigational drug, biologic product, or device is no longer used by the eligible patient; except that coverage may not be denied for a preexisting condition and for coverage for benefits which commenced prior to the time the eligible patient begins use of such drug, biologic product or device”

There are other differences, of course, but they’re mostly wording and Colorado-specific language about state statutes effected. I tend to interpret #1 as having been added to make it sound less as though the FDA approval process is useless, as the Goldwater text does. My guess about #2 is that it was undoubtedly added in order to exclude patients who just want experimental drugs but aren’t interested in enrolling in a clinical trial. Finally, I’m not completely sure how to interpret #3 and would welcome a lawyer’s input (particularly if it’s a health lawyer), but it sounds rather ominous in that it allows insurers to deny new coverage to a patient for a six month period from the time the patient starts use of an investigational drug, but can’t deny coverage for a preexisting condition (i.e., the condition that led the patient to be terminally ill, and any other preexisting conditions) or any benefits that commenced prior to the time the patient starts using an experimental drug or device. On the other hand, to me the language implies that insurance companies can deny coverage for any new problems that come up after the patient starts using experimental therapy, whether caused by that therapy or not. So if the patient develops a complication from the treatment, he’s out of luck. If he happens to be hit by a car, he might be out of luck. Thus, a bill that sounds compassionate appears to have a cruel, punishing twist embedded in it.

Indeed, this law is very “libertarian” in that it says that patients can try an experimental therapy that’s passed phase I trials to phase II or beyond, but anything that happens after that is all on them. (Indeed, right-to-try would allow access to a drug that’s only passed phase I, even if the phase II trial hasn’t accrued a single patient yet, as long as there’s a phase II trial open.) The doctor recommending the treatment is off the hook, no matter how bad his decision to recommend the experimental therapy was. The drug company is off the hook, no matter how many problems the drug might have. The insurance companies appear to be off the hook, complete with a potential loophole to let them refuse to cover various treatments in terminally ill patients.

At this point, I think it’s a good idea for me to remind my readers once again that that these right-to-try laws cover any drug, treatment, or experimental device that has passed phase I clinical trials. Indeed, in the video above, the reporter made a highly misleading statement when she stated that the Colorado “right-to-try” law “only applies to drugs that have been deemed safe by the FDA.” That statement is so wrong it’s not even wrong, as skeptics sometimes like to say. Just because a drug has passed phase I clinical trials does not—I repeat, does not—mean that the drug has been “deemed safe by the FDA.” Phase I trials, also known as “first in human” trials, don’t enroll very many patients. Sometimes it’s as few as 20 patients, sometimes even less. That is not enough to adequately determine safety, nor is it intended to. That’s because phase I trials are designed primarily to identify major side effects and to use a process known as dose escalation to determine what is commonly referred to as the “maximum tolerated dose” (MTD). It is utterly impossible for such a small clinical trial to adequately assess the safety of a drug. All it can do is to make sure there are no unexpected major adverse events, that the expected side effects are tolerable, and that the drug has a side effect profile that isn’t grossly more unsafe than the disease itself. Phase II and phase III trials are needed to confirm safety. That’s why the premature diffusion of unapproved drugs has the potential to increase morbidity from adverse events and even hasten death. One example is amonifide for treating breast cancer. The drug made it through phase I trials, but serious life-threatening hematologic toxicity emerged during phase II trials.

Think of phase I trials as a screening test looking for the most obvious toxicities, with phase II and III studies confirming them. Indeed, even phase III trials can’t always adequately demonstrate that a drug is safe; it’s not uncommon for less common adverse effects not to show up until post-marketing surveillance, when much larger numbers of patients receive the drug. Moreover, only 5% of all cancer drugs that enter clinical testing are ultimately approved for patient use. Among drugs tested in phase II trials, only 30% go on to phase III. So, to equate having passed phase I clinical trials with having been “deemed safe by the FDA” betrays a profound misunderstanding at the heart of the bill of what a phase I trial is and what passing it means. The potential for disaster is there.

The false hope of right-to-try metastasizes to Michigan

I’ll discuss more of what’s wrong with right-to-try laws and how misguided they are, but first I want to take look at the right-to try bills currently under consideration in the Michigan legislature. Oddly enough, I was completely unaware that a right-to-try bill had been introduced into the Michigan legislature until last week, when I got a message from a concerned person. Before that contact, as hard as it is to believe right now, I had heard absolutely nothing about these bills, but I’m a fast learner. I didn’t have much help, though, because there was very little media notice taken of the Senate hearing about this bill other than a Detroit Free Press article that I found days after the hearing and self-serving articles on John Pappageorge’s website touting mistakenly how this bill would allow “access to potentially life-saving treatments.” Either that, or I missed it because I was out of town at TAM in the days leading up to the hearing. Whatever the case, going back to look over the coverage, I found that the Freep article bought in the same compassionate but incorrect framing as was the case in the other states considering such laws:

Arlene Kalley has lived with terminal cancer for years — and with each new drug she uses to keep the disease at bay, her options dwindle.

It doesn’t require manufacturers to provide the drug nor does it require insurers to cover the costs. But it gives patients a “right to try,” said Sen. John Pappageorge, R-Troy, whose first wife died of cancer in 1993.

He introduced the bill earlier this year after speaking with Terry Kalley, a partner with Global Logistics Strategies in Bloomfield Hills.

His wife, Arlene, was taking Avastin in 2011 to keep metastatic breast cancer at bay when the U.S. Food and Drug Administration yanked its approval of the drug, questioning its safety and efficacy.

Ultimately, Arlene Kalley was able to keep taking Avastin because it still was being used to treat other cancers, but the experience got the Kalleys thinking about what could happen if Arlene Kalley’s current treatment is no longer effective one day.

While I can understand why this case might have led the Kalleys to wonder about right to try, I must point out here that Avastin was a very different case than situations envisioned in right-to-try legislation. Specifically, Avastin had undergone randomized clinical trials (RCTs) beyond phase I and had already been approved for other cancers before being approved by the “fast track” approval process for advanced breast cancer. Its approval for advanced breast cancer was based on two RCTs that showed a modest increase in progression-free survival (PFS) when Avastin was added to chemotherapy, but no effect on overall survival (OS). In 2008, based on a program to “fast track” promising drugs that was developed in 1990s, the FDA gave provisional approval to Genentech to market Avastin for metastatic breast cancer with the condition that Genentech had to perform additional studies to verify the results upon which the original approval had been based. At the time, there was a great deal of argument over whether this was a wise decision, particularly given how expensive Avastin is and the lack of evidence that it improved quality of life or overall survival. Unfortunately, the results of those additional clinical trials were very disappointing to all of us who take care of breast cancer patients. The AVADO trial only found an increase in PFS of less than a month when Avastin was added to docetaxel with no increase in OS, while the RIBBON-1 trial found an improvement in PFS of 2.9 months when added to capecitabine, and 1.2 months when added to anthracycline-based chemotherapy. That’s why in July 2010 the FDA advisory committee revoked the fast track approval.

In other words, although I realize that Arlene Kalley was simply worried about what her options would be if her current treatment regimen ceases to keep her cancer in check, in a manner of speaking she is inadvertently comparing apples and oranges in a way that could lead those unfamiliar with the Avastin saga to believe that Avastin and right-to-try are related by anything other than the fact that she has done well on Avastin thus far. I bring this up because the saga of Avastin for breast cancer is relevant to right-to-try bills, but not in the manner implied. Contrary to the arguments made in favor of right-to-try laws that a single phase I trial is enough for a treatment to be deemed “safe,” even though Avastin was FDA-approved for other cancers and provisionally approved for breast cancer, in the subsequent clinical trials for advanced breast cancer there was evidence of harm due to Avastin. That harm likely accounted for why the increase in PFS did not translate into an improvement in OS. Specifically, the drug’s toxicity likely “took back” those gains in PFS. As Fran Visco of the National Breast Cancer Coalition put it, “The FDA should never have approved Avastin for breast cancer to begin with. We don’t see evidence of benefit, but we do see evidence of harm.” And that was just Avastin, not a drug with much less extensive testing, such as the experimental therapies right-to-try bills propose releasing “into the wild,” so to speak.

So what do the Michigan bills SB 991 (Senate) and HB 5651 (House) propose? It’s basically very similar to the Colorado law and the Goldwater Institute boilerplate, with a couple of notable exceptions. For example, SB 991 requires:

A statement in the “written informed consent” for using the experimental drug that informs the patient that “the patient’s eligibility for hospice care may be withdrawn if the patient begins curative treatment and that care may be reinstated if the curative treatment ends and the patient meets hospice eligibility requirements.”

A statement in the “written informed consent” for using the experimental drug that attests that the “patient understands that he or she is liable for all expenses consequent to the use of the investigational drug, biological product, or device and that this liability extends to the patient’s estate, unless a contract between the patient and the manufacturer of the drug, biological product, or device states otherwise.”

The first of these is odd and unnecessary in that hospices tell patients up front that if they undertake curative treatment again they are no longer eligible to be in hospice while undergoing the treatment. Including such a provision in SB 991 strikes me as redundant, a duplication of law and policy that already exists for hospices. The second of these is to me quite objectionable. Not only does it put the patient on the hook for any expenses or debt that he incurs using experimental treatments, but it seems custom-made for drug companies, to make sure that they get their money for experimental therapies administered under “right-to-try,” no matter what, even letting them go after a deceased patient’s estate, something that will frequently be necessary because patients eligible for “right-to-try” by definition have a terminal illness, and the vast majority of even the most promising drugs will likely only prolong their life, not save it. Either way, both of these Michigan provisions make a bad bill even worse.

In fairness, though, there is also a provision that explicitly states that a patient’s heirs are not liable for outstanding debt related to the treatment or lack of insurance and specifies that this act “does not affect any mandatory health care coverage for participation in clinical trials under the insurance code of 1956, 1956 PA 218, MCL 500.100 to 500.8302,” which, unlike the weasely language in Colorado’s law, means that insurance companies must continue to cover all treatments not related to the experimental treatment. Also in fairness, SB 991 does add a provision to the usual Goldwater Institute boilerplate that states that “an official, employee, or agent of this state shall not block or attempt to block an eligible patient’s access to an investigational drug, biological product, or device” by adding that “counseling, advice, or a recommendation consistent with medical standards of care from a licensed health care provider is not a violation of this section.” As faculty at a state institution, I would have been very worried about the part about not blocking access as a provision that might get me in trouble if I were simply to voice my medical opinion.

There was also a curious substitution resulting in a “substituted bill” for SB 991 that stops referring to “terminal illnesses” and instead refers to such illnesses as “advanced illnesses”:

(a) “Advanced illness” means a disease or medical or surgical condition with significant functional impairment that is not reversible even with administration of current federal drug administration approved and available treatments that is expected to result in death or a state of unconsciousness from which recovery is not expected. For purposes of this act only, advanced illness has the same general meaning as terminal illness has in the medical community.

For the life of me, I can’t figure out why this change was made, when the substituted bill states that for the purposes of this bill “advanced illness has the same general meaning as terminal illness has in the medical field.” I can’t help but get a sneaking suspicion, which could be wrong, that perhaps the bill’s sponsors are already thinking ahead to eventually expand eligibility for right-to-try to patients who are not terminally ill by laying the groundwork to have “advanced illness” associated with right-to-try rather than just terminal illness. I could be wrong, of course. Alternatively maybe there’s some regulatory or political reason for the substitution. Either way, the Michigan right-to-try bills are in some ways worse and in some ways not as bad as the Colorado right-to-try law. That doesn’t change how much these laws are flawed in their very conception.

The problem with right to try

I can understand the desperation of families, at least, facing the loss of a loved one to a terminal disease, be it cancer or something just as bad or even worse, such as amyotropic lateral sclerosis (ALS), more commonly known to the public as Lou Gehrig’s disease. After all, it was only five years ago that my wife and I faced the death of her mother from metastatic triple negative breast cancer, including brain metastases. Knowing, as all cancer doctors do, that it could happen to me (particularly now that I’m on the wrong side of 50), I can’t even guarantee that I wouldn’t be tempted by the siren call of right-to-try were one of these bills, or some variant thereof, to be passed into law in Michigan and I later was diagnosed with a terminal illness.

Even so, when people ask, “What’s the harm? and “How can it get worse?” I know that there is harm and it can get worse. If there’s anything worse than dying prematurely of a terminal illness, it’s accelerating your demise, suffering unnecessarily during the little time you have left, and/or emptying your bank account while doing either or both of these things. Compassion impels us to want to help terminally ill people in any way we can, but a less emotional analysis of right-to-try bills, coupled with a knowledge of the science and conduct of clinical trials reveals that these laws, as currently constituted, are almost universally a bad idea. Indeed, with such a low bar for a drug or device to qualify for right-to-try (a single phase I trial), it’s almost guaranteed that such laws are highly unlikely to help, at the cost of a not-insignificant risk of causing harm. These laws would be less odious if the bar had been raised a bit, for instance requiring that at least a phase II trial before a drug is eligible, but that’s not what any of these bills propose.

Right-to-try laws also provide false hope. For one thing, these laws rest on the faulty assumption that there are all sorts of “miracle drugs” out there that can save the lives of terminally ill patients if only the FDA would get out of the way. This assumption becomes rapidly apparent perusing the Goldwater Institute’s pages on right to try, which is packed with loaded language about the FDA and terminally ill patients, with every experimental drug apparently “potentially life-saving” and patients dying because they can’t get these drugs. Besides the greater likelihood of resulting in patient harm than help, contrary to what their advocates promise, right-to-try laws won’t deliver increased access to experimental drugs. The reason, as Jann and I have both explained at more length before, is because the federal government, through the FDA, controls drug approval, and federal law trumps state law. State right-to-try laws have no power over the FDA, and nothing states can do can compel the FDA to abide by their right-to-try laws. Moreover, drug companies are understandably reluctant to allow just anyone the use of investigational drugs still in clinical trials, because if something bad happens it could very well affect their application for approval:

However, companies and regulators alike have expressed some hesitancies about the program. For companies, expanded access means letting products out of tightly controlled and heavily monitored environments, potentially subjecting the product to incorrect use and previously-unknown adverse events, which would still need to be reported to FDA. Such incidents could potentially raise questions for regulators, thereby harming the chance of a product getting to market. Further, some companies have expressed their fears about expanded access programs robbing their clinical trials of some patients, which could reduce the statistical validity of a trial and potentially harm other patients by delaying a drug’s path to market.

Another issue is a practical one. Manufacturing a new drug for the first time is expensive, which is why, quite often, only enough is manufactured to supply approved clinical trials to be used to support an application for FDA approval. “On-demand” manufacturing would not be easy to implement, particularly if enough patients asked for the drug under right-to-try. This could be a particular problem for small biotechnology companies, which often can barely scrape together the capital to do the necessary clinical trials to support FDA approval. Given that these small biotech companies are often the most innovative and least likely to be seeking approval for “me-too” drugs, the effect of right-to-try on the pharmaceutical industry’s already weak innovation could be significant.

It’s also important to note that right-to-try laws are more about ideology than science. Proponents and supporters of right-to-try tend to use arguments very similar to those used by the “health freedom movement” that rely on questions like, “Who owns you?” and appeals to the belief that the government shouldn’t tell people how they should manage their health. For instance, the Alliance for Natural Health USA, a key “health freedom” organization that advocates relaxing laws regulating the practice of medicine, the better to let more quackery flourish, is very much in favor of a federal version of “right-to-try,” which is every bit as much a bad idea as the state right-to-try laws, given that it would actually do something. The Goldwater Institute, in an article promoting right-to-try, gives itself away by bemoaning the expansion of FDA authority in the 1960s by the Kefauver-Harris Amendments that required that the FDA not just require demonstration of safety but of efficacy as well before approving new drugs. This expansion of FDA power was in reaction to the thalidomide debacle, leading the Goldwater Institute to make the bizarre argument that because the issue with thalidomide was a safety problem, not an efficacy problem and because thalidomide was never approved in the US (mainly due to the FDA, let’s not forget), the expansion of FDA power in response to the thalidomide debacle was “unwarranted.”

Unfortunately, right-to-try bills and laws are nothing but feel-good measures that provide the illusion of actually doing something without actually doing anything substantive to help desperately ill patients, particularly given that the FDA already has an expanded access program to allow patients to use drugs outside of clinical trials. There are estimated to be 1,000 requests per year now, and it is uncommon for the FDA to deny a request for expanded access. Indeed, in FY2013, only three such requests were denied; in 2012, four; in 2011, one; and in 2010, sixteen. If, as proponents of these bills believe, expanded access programs aren’t easy enough to access, the answer is not to pass state right-to-try laws. It’s to reform the FDA’s expanded use program, something that’s occurred before and is ongoing, just as the FDA has developed a “fast-track” approval program, the same one under which Avastin was approved.

As David Kroll pointed out, true compassionate use reform will require that we as a society come to an agreement about the balance between access and scientific rigor, realizing that unapproved drugs, particularly the biologicals, such as monoclonal antibodies (which are very tricky to manufacture), are often in short supply. It doesn’t help terminally ill patients if patients demanding right-to-try put companies in a dilemma in which they either surrender some of their precious stock of investigational drug for “right-to-try” requests, thus endangering the company’s ability to conduct proper clinical trials, nor does it help patients to spend their life’s savings on investigational drugs that are unlikely to help them and could hurt them. Although their supporters are well-meaning and sincerely think they are helping the most desperate of their fellow human beings, right-to-try laws are a cruel sham perpetrated on terminally ill patients and should be opposed wherever they metastasize.